ABSTRACT Muscle satellite cells are the most studied cells in skeletal muscle. They fulfill many of the requirements of tissue-specific stem cells, including the ability to self-renew and to differentiate into multiple cell types. In addition to satellite cells, other myogenic progenitors have been isolated from both human and mouse skeletal muscle. These 'alternative' myogenic progenitors are distinct from satellite cells and many appear associated to the microvasculature or in the interstitial spaces between myofibers. One of these 'alternative' myogenic cell populations is the so-called 'side population' (SP). Our studies in human muscle have proposed that SP cells secrete factors (such as BMP4) that induce the proliferation of myogenic progenitors expressing receptors for these factors (BMP-receptor 1a, BMPR1a). In the current application, we will elucidate the ties between human muscle SP cells and BMPR1a+ progenitors, study whether forced expression of BMPR1a in muscle SP cells leads to their activation and commitment to the myogenic lineage, investigate if loss of BMPR1a+ expression in skeletal muscle progenitors expressing Myf5 or Pax3 will lead to muscle pathology, and determine in a mouse model whether muscle SP cells or BMPR1a+ progenitors are 'stem'-like cells with intrinsic high-replicative capacity. The Specific Aims of these studies, which involve both human and mouse cells, are: Aim 1: Determine if human muscle SP cells are 'ancestors' of BMPR1a+ myogenic progenitors; Aim 2: Assess if forced expression of BMPR1a in human muscle SP cells is necessary and sufficient to induce their proliferation and specification towards the myogenic lineage; Aim 3: Investigate if BMPR1a+Myf5+ or BMPR1a+Pax3+ progenitors are important for muscle development and participate in muscle regeneration in post-natal life; Aim 4: Use the m-TERT GFP model to identify telomerase-expressing cells in skeletal muscle and determine their relationship to muscle SP, BMPR1a+ cells or other muscle 'stem' cells. These studies will unveil the function of BMPR1a expression in muscle progenitors and unravel the relationship between human muscle SP and BMPR1a-expressing cells. Mouse and human studies will synergize with one another, to define the significance and importance of each myogenic cell population in both species.